To clarify the joint effects of environmental and genetic factors in the etiology of breast cancer, the NIEHS Sister Study will prospectively study of 50,000 sisters of women who have had breast cancer. Such sisters have about twice the risk of developing breast cancer as other women. The frequency of any relevant genes and shared risk factors will also be higher, enhancing the statistical power of the study to detect risks. Sisters are highly motivated and response rates and compliance over time are expected to be high. Thus, studying sisters will enhance our ability to understand the interplay of genes and environment in breast cancer risk and to identify potentially preventable risk factors. The prospective design will allow us assess exposures before the onset of disease thus avoiding biases common to retrospective studies and aiding in causal interpretation. The study will create a framework from which to test new hypotheses as they emerge. [unreadable] [unreadable] A diverse cohort of volunteer women from throughout the US and Puerto Rico between the ages of 35 and 74 who have a sister with breast cancer but do not have breast cancer them selves are being recruited. Recruitment strategies are designed to maximize inclusion of minorities and high-risk women. Data on potential risk factors and current health status are collected using computer assisted telephone interviews and mail questionnaires. Blood, urine, and environmental samples are collected and banked for future use in nested studies of women who develop breast cancer (or other diseases) and a sample of those who don't. The cohort will be followed prospectively for 10 or more years. Address changes, vital status, and major health changes are updated annually. More detailed health and exposure updates will be collected at 2-year intervals. Medical records and tumor tissue (for breast cancer cases) will be retrieved for those who develop cancer or other conditions of interest. 1500 new cases of breast cancer are expected to occur in the cohort after five years. Analyses will assess the independent and combined effects of environmental exposures and genetic polymorphisms that affect estrogen metabolism, DNA repair, and response to specific environmental exposures. Future analyses will focus on known and potential risk factors (e.g. smoking, occupational exposures, alcohol, diet, obesity) and include measurement of phthalates, phytoestrogens, and metals in blood and urine, insulin, growth factors, vitamins and nutrients, and genes. The cohort will be used to also study risk for other diseases (e.g. heart disease, osteoporosis, other hormonal cancers, and autoimmune diseases) as well as explore genetic and environmental effects on prognosis. A pilot phase began August 2003 involving women from 4 metropolitan areas of the US selected for their geographic and ethnic diversity in order to assess a range of recruitment strategies and plan for a larger scale national effort. The study began recruiting nationally in October 2004. All study materials were made available in Spanish in mid-September, 2005.[unreadable] [unreadable] To date more than 41,000 women have enrolled in the study and over 32,000 have completed all baseline activities. The response rates for annual updates range from 90-98%. Biennial follow-up questionnaires will be mailed in late 2007.[unreadable] [unreadable] Using an analytic dataset comprising the first 21,000 women who completed all baseline activities, we have been exploring relationships among breast cancer risk factors and carrying out descriptive analyses, with results on childhood factors and adult obesity presented at a national meeting. This year a methodlogical paper describing the statistical advantages of the sampling design used in the Sister Study was published in the epidemiological literature.